17β-Ethynyl-3,17α-estradiol and derivatives thereof

ABSTRACT

17β-ethynyl-3,17α-estradiol and derivatives thereof are prepared by epimerization of 17-acyl esters of 17α-ethynyl-3,17β-estradiol 3-ethers. 17α-ethynyl-3,17α-estradiol and its derivatives are active as post-coital antifertility agents and inhibit the growth of or reduce the size of the prostate gland and the seminal vesicle.

This is a continuation-in-part of application Ser. No. 393,873, filedSept. 4, 1973, now U.S. Pat. No. 3,983,112.

BACKGROUND OF THE INVENTION

Ethynylation of 17-keto steroids having a normal configuration at C₁₄generally proceeds by attack of the reagent at the sterically lesshindered α-side of the keto group which results almost exclusively inthe production of the 17α-ethynyl-17β-ol derivative. Steroidal productsresulting from attack at the 17β-side of the keto group have beenreported, but the yields of these compounds generally have been verylow. By means of the present invention, a novel process for thepreparation of 17β-ethynyl-3,17α estradiol and derivatives thereof isprovided.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to 17β-ethynyl-3,17α-estradiol and derivativesthereof. The compounds are 19-norpregna-1,3,5(10)-trien-20-yn-3,17α-dioland derivatives thereof and can be represented by the general formula:##STR1## wherein R₁ is hydrogen, lower alkyl of from 1 to 5 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, isopropyl, pentyl,and the like; cycloalkyl having 4 to 6 carbon atoms such as, forexample, cyclobutyl, cyclopentyl and cyclohexyl, and a lower acyl grouphaving 2 to 6 carbon atoms such as, for example, acetyl, propionyl,butyryl, valeryl and the like; and R₂ is hydrogen or a lower acyl grouphaving 2 to 6 carbon atoms. Preferred among the above compounds arethose compounds wherein R₁ is hydrogen cycloalkyl or lower alkyl, having2 to 5 carbon atoms and R₂ is hydrogen or lower acyl.

In general, the compounds of the present invention possess very lowestrogenicity, but are nevertheless physiologically active agents. Theyexhibit preimplantive antifertility activity and also reduce the size ofthe prostate gland and the seminal vesicle.

17β-ETHYNYL-3,17α-ESTRADIOL [I.E.,19-NORPREGNA-1,3,5(10)-TRIEN-20-YN-3,17α-DIOL] AND ITS DERIVATIVES WHICHARE THE SUBJECT OF THIS INVENTION CAN BE PREPARED BY EPIMERIZATION OF17-ACYL ESTERS OF 17α-ETHYNYL-17β-DIOL 3-ETHERS [I.E., 17-ACYL ESTERS OF17α-PREGNA-1,3,5(10)-TRIEN-20-YN-3,17β-DIOL 3-ETHERS] (Formula II) onactivated alumina: ##STR2## wherein R₁ is lower alkyl or cycloalkyl andR₂ is lower acyl. A solution of a 17α-ethynyl-3,17β-diol 17-acyl ester3-ether of Formula II is treated with activated alumina to effectepimerization. Generally, a non-polar solvent such as benzene, toluene,carbon tetrachloride, tetrahydrofuran, and the like, is employed as thesolvent. The reaction is carried out with activated alumina, having anactivity of about 1, for several days. It is preferred to carry out thereaction for from about 2 to 10 days. Neutral, basic or acidic aluminamay be employed, but it is preferred to carry out the reaction withneutral or basic alumina. The reaction can be carried out at atemperature between about room temperature and 80° C., but it ispreferred to carry out the reaction at room temperature. Generally, aratio of alumina to steriod ranging from 1:100 to 1:20 is employed. Thereaction can be carried out by allowing the solution of the steroid tosit on a column of alumina or the solution can be agitated with a slurryof alumina in a suitable reaction vessel. When the treated mixture iseluted with solvents of increasing polarity, e.g., increasingproportions of ethyl acetate in benzene, a mixture of products isobtained which includes (a) a Δ¹⁶ -enyne (Formula III). ##STR3## (b) thestarting 17-acyl derivative; (c) a mixture of the epimerized product,i.e., 17β-ethynyl-17α-ol of Formula I and an unsaturated aldehyde(Formula IV). ##STR4## and (d) a 17α-ethynyl-17β-ol of Formula IIwherein R₁ is as previously defined.

The mixture of the 17β-ethynyl-17α-ol and the aldehyde can be separatedeither by chromatography followed by fractional crystallization or byremoving the aldehyde through formation of a suitable Schiff base suchas a semi-carbazone, for example.

The epimerized product of Formula I is generally obtained as an etherdepending upon the particular starting material employed. The 3-olcompounds, i.e., those compounds wherein R₁ is hydrogen can be preparedby removal of the ether function. De-etherification can be carried outunder neutral, basic or mildly acidic conditions. For example, themethyl ether (R₁ is CH₃) can be treated with a suitable demethylatingagent such as diphenyl phosphide or arsenide anion, a lithium halide oran alkyl Grignard reagent. The preferred demethylating agent is an alkylGrignard reagent of the type RMgX, wherein R is a lower alkyl group of 1to 5 carbon atoms and X is chlorine, iodine or bromine. Best results areobtained where methyl magnesium iodide is employed as the demethylatingagent. The reaction is generally carried out for several hours at atemperature between room temperature and about 190° C. Alternatively,the 3-ol compounds can also be prepared by treating the methyl etherwith boron tribromide in a suitable solvent such as dichloromethane, forexample, at a temperature of about -10°- 0° C.

Conversely, the free 17β-ethynyl-3,17α-estradiol can be converted tovarious ethers by heating it with the appropriate alkyl or cycloalkylhalide, such as ethyl bromide, or cyclopentyl bromide and potassiumcarbonate in a suitable solvent such as methanol or ethanol. The variousesters at C₃ and C₁₇ can also be prepared by heating the17β-ethynyl-3,17α-estradiol with the anhydride of a lower aliphaticcarboxylic acid, such as acetic anhydride, for example.

In an alternate method 17β-ethynyl-3,17α-estradiol and its ethers can beobtained by the reductive opening of the corresponding 16α,17α-epoxycompound (Formula V). ##STR5## wherein R₁ is as previously defined. Thereduction can be effected by employing any of the general epoxidereducing methods known in the art. It is preferred, however, to carryout the reaction with a metal hydride such as lithium aluminum hydride,for example. In the apoxide reduction method the 3-acyl substitutedepoxides yield 17β-ethynyl-3, 17α-estradiol directly whereas the 3-etherderivatives of the epoxide yield the corresponding 3-ethers of17β-ethynyl-3, 17α-estradiol which can be converted to 17β-ethynyl-3,17α-estradiol by removal of the 3-ether function.

The 17β-ethynyl-3,17α-epoxides of Formula V are in turn prepared by theepoxidation of the corresponding Δ¹⁶ -enynes with a suitable per acidsuch as meta-chloroperbenzoic acid, for example, according to thefollowing reaction scheme: ##STR6## The Δ¹⁶ -enynes can be prepared bydeacylation of 17α-ethynyl-3,17β-estradiol 3-ether, 17-acylate onalumina or by dehydration of 17α-ethynyl-3,17β-estradiol,3-ether or theacyl derivative in pyridine with either phosphorous oxychloride orthionyl chloride.

The following examples illustrate the invention and are not to beconstrued as imposing any limitations thereon.

Preparation of Starting Material Preparation A 3-methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17β -ol acetate

A mixture of 3-methoxy-19-nor-17α -pregna-1,3,5(10)-trien-20-yn-17β -ol(10 g.) and acetic anhydride (200 ml.) is heated at reflux for 3 hours.The mixture is then cooled, poured into ice water (2,000 ml.) andstirred for several hours until the excess acetic anhydride isdecomposed. The precipitate which forms is filtered, washed free fromacid with water, and dried. Upon crystallization from methanolethylacetate, 3-methoxy-19-nor-17α -pregna-1,3,5(10)-trien-20-yn-17β -olacetate is obtained, m.p. 162°-163° C.

When in the above procedure 19-nor-17α-pregna-1,3,5(10)-trien-20-yn-3,17β -diol is employed in place of thecorresponding 3-methoxy compound, 19-nor-17α-pregna-1,3,5(10)-trien-20-yn- 3,17β -diol diacetate is obtained.

When in the above procedure propionic anhydride, butyric anhydride, orvaleric anhydride is employed in place of acetic anhydride, thecorresponding 17-acyl esters 3-ethers of 17α -ethynyl-3,17β -estradiolare obtained, e.g., 17α -ethynyl-3,17β -estradiol 3-methyl ether 17propionate, 17α -ethynyl-3,17β -estradiol 3-methyl ether 17 butyrate,17α -ethynyl-3,17β -estradiol 3-methyl ether 17-valerate respectivelyare obtained.

Preparation B 19-nor-17α -pregna-1,3,5(10)-trien-20-yn-3,17β -diol17-acetate

A solution of 19-nor-17α -pregna-1,3,5(10)-trien-20-yn-3,17β -dioldiacetate (5 g.) in methanol (300 ml.) is treated with a solution ofpotassium carbonate (2.5 g.) in water (20 ml.) and the resulting mixtureis stirred at room temperature for 5 hours. The methanolic solution isthen neutralized with dilute hydrochloric acid and evaporated to drynessunder reduced pressure. The residue is extracted with chloroform and thechloroform layer is washed with water and dried over sodium sulfate.Upon removal of the solvent, a solid residue is obtained which iscrystallized from benzenehexane, m.p. 211°-212° C.

Preparation C 19-nor-17α-pregna-1,3,5(10)-trien-20-yn-3,17β-diol3-acetate

A solution of 19-nor-17α-pregna-1,3,5(10)-trien-20-yn-3,17β-diol (1.0g.) in pyridine (5 ml.) is treated at room temperature with aceticanhydride (2.5 ml.) for 1 hour. The reaction mixture is then poured intoan ice-water mixture and extracted with ether. The ether layer is washedwith water, dried over Na₂ SO₄, and the solvent is removed under vacuum.The residue obtained is crystallized from benzenehexane, to yield19-nor-17α-pregna-1,3,5(10)-trien-20-yn-3, 17β-diol 3-acetate, m.p.152°-153° C.

When in the above procedure propionic anhydride, butyric anhydride orvaleric anhydride is employed in place of acetic anhydride, thecorresponding 3-acyl ester of 17α-ethynyl-3,17β-estradiol is obtained.

Preparation D 3-acetoxy-19-norpregna-1,3,5(10),16 -tetraen-17-yne

A solution of 17α-ethynyl-3,17β-estradiol 3-acetate (4.5 g.) in drypyridine (40 ml.) is treated with freshly distilled phosphorousoxychloride (2.45 ml.) and heated at reflux for 2 hours. The resultingmixture is then cooled and poured into ice water containing concentratedhydrochloric acid (50 ml.). The mixture is extracted with ether and theorganic phase is washed with water, 10% sodium bicarbonate and water andthen dried over Na₂ SO₄. Upon evaporation of the solvent, 2.95 g. of asolid residue are obtained. Purification of the residue on a column ofsilica followed by recrystallization from methanol affords3-acetoxy-19-norpregna-1,3,5(10), 16-tetraen-17-yne, m.p. 114°-115° C.

When in the above procedure 17α -ethynyl-3,17β -diol 3-methyl ether isemployed in place of 3-acetoxy-19-norpregna-1,3,5(10)-16-tetraen-17-ynethe corresponding Δ¹⁶ -enyne,3-methoxy-19-norpregna-1,3,5(10),16-tetraen-17-yne, m.p. 156°-157° C. isobtained.

EXAMPLE I 3-methoxy-19-norpregna-1,3,5(10-trien-20-yn-17α -ol

A solution of 3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17β -olacetate (10 g.) in benzene (50 ml.) is allowed to sit on a column ofneutral alumina (Woelm, grade I, activity 1; 1,000 g.) for 5 days. Uponelution with benzene containing increasing portions of ethyl acetate, alarge number of fractions (125 ml. each) is collected. These are pooledinto three major fractions on the basis of thin layer chromatographyexamination.

Fraction (i) 3.5 g., represents the fastest moving material consistinglargely of 3-methoxy-17-pregna-1,3,5(10), 16-tetraen-20-yn-3-ol.

Fraction (ii) consists of four components. The first one is3-methoxy-19-nor-17α -pregna-1,3,5(10)-trien-20-yn-17β -ol acetate; thesecond one is the epimerized product:3-methoxy-19-norpregna-1,3,5(10)-triene-20-yn-17α -ol; the third one is3-methoxy-19-norpregna-1,3,5(10), 17(20)-tetraen- 21-al; and the fourthone is 3-methoxy-19-nor-17α -pregna-1,3,5(10)-trien-20-yn-17β -ol.

Fraction (iii) is mainly 3-methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17β -ol.

Careful rechromatography of fraction (ii) on silicic acid with ethylacetate in benzene affords3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol in 5% yield. Uponrecrystallization from methanol, a product having m.p. 136°-137° C.,(α)_(D).sup. 24 + 71.8 (C, 1.0CHCl.sub. 3) is obtained.

EXAMPLE II 19-norpregna-1,3,5(10)-trien-20-yn-3,17α -diol

In a three-necked, 2 liter round bottomed flask equipped with a magneticstirrer, a gas inlet tube and an air condenser, is charged an etherealsolution of methyl magnesium iodide (2.6 molar, 278 ml.) followed by3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol (11.8 g.) under anatomsphere of argon. The mixture is heated slowly in an oil bath to 175°C. and maintained at that temperature for an additional three hours. Theflask is then cooled in a dry ice-acetone bath. A mechanical stirrer isintroduced to break up the solidified foamy mass in the flask and asaturated solution of NH₄ Cl (500 ml.) is added carefully (highlyexothermic). The mixture is adjusted to pH 5 and extracted with ethylacetate. The ethyl acetate layer is washed with water, dried over Na₂SO₄, and a crystalline residue (16 g.) is obtained upon removal of thesolvent. The residue is chromatographed on a column of neutral silica(800 g.) and eluted with 3 to 5% ethyl acetate in benzene to afford 10.0g. of solid material. Decolorization with charcoal and recrystallizationfrom acetone-hexane yields 7.9 g. of19-norpregna-1,3,5(10)-trien-20-yn-3,17α -diol, m.p. 210°-212° C.,(α)_(D).sup. 25 + 68° C. (C, 1.0, dioxane).

EXAMPLE III 3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol

Lithium aluminum hydride (10 g.) is added to a solution of 3-methoxy-16α,17α -epoxy-19-norpregna-1,3,5(10)-trien-20-yne (10 g.) intetrahydrofuran (800 ml.) and the resulting mixture is stirred andheated at reflux for 1.5 hours under nitrogen. The mixture is cooled inan ice-bath, and to it, in succession, water (10 ml.) 15% NaOH solution(10 ml.) and again water (30 ml.) are added very carefully with vigorousstirring. The granular precipitate of aluminum oxides is removed byfiltration and washed several times with ether. The combinedtetrahydrofuran and ether solutions are evaporated to dryness. Theresidue is chromatographed on neutral silica (500 g.) and eluted withincreasing proportions of ethyl acetate in benzene. The first product tocome out of the column is 17-pregna-1,3,5(10), 16-tetraen-20-yn-3-olmethyl ether; the second one is3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol; and the remainderis a mixture of two epimeric 17-ethynyl-16-ols.

Recrystallization of 3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α-ol from methanol affords a product having m.p. 136°-137° C., which isidentical with that obtained by the epimerization procedure described inExample I.

EXAMPLE IV 3-cyclopentoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol

A solution of 19-norpregna-1,3,5(10)-trien-20-yn-3,17α -diol (6.0 g.) inethanol (200 ml.) is added to a suspension of K₂ CO₃ (8.0 g.) incyclopentyl bromide (12 g.) and the resultant mixture is heated toreflux under nitrogen for 4 hours. The reaction mixture is then cooled;the solvent is removed under reduced pressure, and the residue ispartitioned between water and ether. The organic layer is washed, driedover Na₂ SO₄ and the ether is removed under vacuum. The glassy residueis purified by chromatography on neutral silica (400 g.). Elution with0.5% ethyl acetate in benzene affords 6.0 g. of solid material. Uponrecrystallization from methanol,3-cyclopentoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α -ol, m.p.113°-114° C., (α).sub. D²⁶ + 62.5° C. (C, 1.0, CHCl₃) is obtained.

EXAMPLE V 3-methoxy-16α-17α-epoxy-19-norpregna- 1,3,5(10) -trien-20-yne

To a solution of 3-methoxypregna-1,3,5(10),16-tetraen-17-yne (5.5 g.) inchloroform (250 ml.) at room temperature is added with stirring asolution of m-chloroperbenzoic acid (8.0 g.) in chloroform (300 ml.)over a period of 30 minutes. The stirring is continued for an additional5 hours after which a solution of NaHSO₃ (10%) is added to destroy theexcess peracid. The chloroform solution is then washed successively witha solution of sodium bicarbonate (10%, 3× 250 ml.) and water. Afterdrying over sodium sulfate, the chloroform is removed by distillationand the residue chromatographed on neutral silica gel. Upon elution withbenzene-petroleum ether (35:65) unreacted-enyne is obtained. Elutionwith benzene-petroleum ether (50:50) affords the epoxide (2.85 g.). Uponrecrystallization from methylene chloride-methanol a sample having m.p.199.5° C., (α).sub. D²⁶ + 103° C. (C, 0.5, CHCl₃) is obtained.

EXAMPLE VI 3,17α-diacetoxy-19-norpregna-1,3,5(10)-trien-20-yne

When the procedure of Preparation A is employed using19-norpregna-1,3,5(10)-trien-20-yn-3,17α-diol as the starting material,3,17α-diacetoxy-19-norpregna-1,3,5(10)-trien-20-yne, m.p. 205°-208° C.(d), (α).sub. D²⁴ + 47° C. (C, 0.9, CHCl₃) is obtained.

When in the above procedure3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-3,17α-diol is employed inplace of the corresponding 3-methoxy compound,3-methoxy-19-norpregna-1,3,5 (10)-trien-20-yn-17α-ol acetate isobtained.

When in the above procedure propionic anhydride, butyric anhydride orvaleric anhydride is employed in place of acetate anhydride, thecorresponding 3,17-diacyl esters of 17β-ethynyl-3,17α-estradiol areobtained, e.g., 17β-ethynyl-3,17α-estradiol3,17α-dipropionate,17β-ethynyl-3,17α-estradiol-3,17.alpha.-dibutyrate,17β-ethynyl-3,17α-estradiol-3,17α-divalerate respectively are obtained.

EXAMPLE VII 3-acetoxy-17α-hydroxy-19-norpregna-1,3,5(10)-trien-20-yne

When the procedure of Preparation C is employed using19-norpregna-1,3,5(10)-trien-20-yn-3,17α-diol as the starting material,3-acetoxy-17α-hydroxy-19-norpregna-1,3,5 (10)-trien-20-yne, m.p.131°-132° C., (α).sub. D²⁴ + 64.2° C. (C, 1.0, CHCl₃) is obtained.

When in the above procedure propionic anhydride, butyric anhydride orvaleric anhydride is employed in place of acetic anhydride, thecorresponding 3,17α-diol 3-esters of 17β-ethynyl-3,17α-estradiol areobtained, e.g., 17β-ethynyl-3,17α-estradiol 3-propionate,17β-ethynyl-3,17α-estradiol-3-butyrate,17β-ethynyl-3,17α-estradiol-3-valerate respectively are obtained.

EXAMPLE VIII 19-norpregna-1,3,5(10)-trien-20-yn-3,17α-ol

When in the procedure of Example III,3-acetoxy-16α,17α-epoxy-19-norpregna-1,3,5(10)-trien-20-yne is employedas the starting material, the product obtained is19-norpregna-1,3,5(10)-trien-20-yn-3,17α-ol, m.p. 210°-212° C., which isidentical with that obtained from Example II.

EXAMPLE IX 19-norpregna-1,3,5(10)-trien 20-yn-3,17α-diol

A solution of 3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α-ol (0.5g.) in dichloromethane (25 ml.) is treated with stirring at -10° C. withboron tribromide (1.7 ml.) and the resulting solution is allowed to stirat -10° C. under nitrogen for 1.5 hours. The reaction mixture is thentreated with water and the organic phase is washed with dilute NaHCO₃solution and water and then dried over Na₂ SO₄. The residue obtainedupon removal of the solvent is chromatographed on silica and eluted with3 to 5% ethyl acetate in benzene to afford a product having an m.p. of210°-212° C., which is identical with the product obtained by theprocedure described in Example II.

As indicated above, the 17β-ethynyl-17α-estradiols of this invention areuseful as post-coital anti-fertility agents and inhibit the growth of orreduce the size of the prostate gland and the seminal vesicle.

In order to determine the preimplantive antilittering effect of a givencompound, a female animal, such as a rat, mouse, or hamster, forexample, is fed the compound to be tested. Adult female rats are smeareddaily and at the period immediately preceding estrus (proestrus) theyare caged overnight with male rats of proven fertility. On the followingmorning, the females are examined for the presence of sperm in theirvaginal washings. The day on which sperm are found constitutes the firstday of pregnancy (Day 1). The rats are fed the test compound dissolvedin sesame oil by gavage on day 1 through the sixth day of pregnancy andare sacrificed on the fourteenth day. The uterii are then examined forimplantation and resorption sites. A control group is similarly treatedexcept that the compound is not administered.

The 17β-ethynyl-17α-estradiols are effective when administered inamounts ranging from about 1- 50 mg./kg.

In order to determine the prostate reducing activity mature male rats ofthe Wistar strain, 180-200 g., are injected (S.C.) with the test drugdaily for three weeks. At the end of this period, the total prostate andseminal vesicles are removed and weighed. Five rats are used for eachdose group. Controls receive only the vehicle. Results are expressed asthe percentage reduction induced by the test drug compared to thecontrols. This is calculated by dividing the mean weight of the tissueof animals dosed with the test drug by that of the controls.

An example of the prostate reducing activity of the novel steroids maybe illustrated by studies carried out with3,17α-dihydroxy-19-norpregna-1,3,5(10)-trien-20-yne. A carefulexamination of the organs of the sacrificed male rats indicates thattreatment with 2-5 mg/kg will reduce the weight of the prostate gland by20-42%. In addition, the weight of the seminal vesicle is reduced by34-56%. As little as 0.5 mg/kg will reduce the weight of the prostate by13.75% and the seminal vesicle by 11.8%.

The amount of a given compound to be employed in a given instance willdepend on the species being tested. The specific dose and regimenutilized will depend not only on the species being treated, but also onthe compound chosen. An effective dose for a particular species andcompound can be readily determined by routine clinical and laboratoryscreen.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R₁ ishydrogen, lower alkyl having 2 - 5 carbon atoms, cycloalkyl, or loweracyl having 2 - 6 carbon atoms and R₂ is hydrogen or lower acyl having2 - 6 carbon atoms.
 2. The compound of claim 1 wherein R₁ is hydrogen orlower alkyl and R₂ is hydrogen or lower acyl.
 3. The compound of claim 1wherein R₁ is lower alkyl and R₂ is lower acyl.
 4. The compound of claim1 wherein R₁ is lower acyl and R₂ is hydrogen.
 5. The compound of claim1 which compound is 19-norpregna-1,3,5(10)-trein-20-yn-3,17α-diol. 6.The compound of claim 1 which compound is3-cyclopentoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α-ol.
 7. Thecompound of claim 1 which compound is3,17α-diacetoxy-19-norpregna-1,3,5(10)-trien-20-yne.
 8. The compound ofclaim 1 which compound is3-acetoxy-17α-hydroxy-19-norpregna-1,3,5(10)-trien-20-yne.
 9. Theprocess for the preparation of a compound of claim 1 of the formula:##STR8## which comprises treating a compound of the formula: ##STR9##with a metal hydride, wherein R₁ is hydrogen, lower alkyl having 1 - 5carbon atoms or cycloalkyl.
 10. The process for the preparation of acompound of Claim 1 of the formula: ##STR10## which comprises treating acompound of the formula: ##STR11## with a metal hydride, wherein R₁ ishydrogen or lower acyl.
 11. The process of claim 9 wherein the metalhydride is lithium aluminum hydride.
 12. The process of claim 10 whereinthe metal hydride is lithium aluminum hydride.
 13. The process of claim11 wherein R₁ is lower acyl.
 14. A method of inhibiting fertility infemale animals which comprises orally administering to a female animalan effective non-toxic amount of a compound of claim 1 of the formula:##STR12## wherein R₁ is hydrogen, lower alkyl having 1 - 5 carbon atoms,cycloalkyl or lower acyl, and R₂ is hydrogen or lower acyl.
 15. Themethod of claim 14 wherein R₁ is hydrogen or lower alkyl and R₂ ishydrogen or lower acyl.
 16. The method of claim 14 wherein R₁ is loweralkyl and R₂ is lower acyl.
 17. The method of claim 14 wherein R₁ islower acyl and R₂ is hydrogen.
 18. The method of claim 14 wherein thecompound is 19-norpregna-1,3,5(10)-trien-20-yn-3,17α-diol.
 19. Themethod of claim 14 wherein the compound is3-cyclopentoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α-ol.
 20. The methodof claim 14 wherein the compound is3-methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17α-ol.
 21. The method ofclaim 14 wherein the compound is3,17α-diacetoxy-19-norpregna-1,3,5(10)-trien-20-yne.
 22. The method ofclaim 14 wherein the compound is3-acetoxy-17α-hydroxy-19-norpregna-1,3,5(10)-trien-20-yne.
 23. Themethod of inhibiting the growth of the prostate gland which comprisesorally administering to an animal an effective non-toxic amount of acompound of Claim 1 of the formula: ##STR13## wherein R₁ is hydrogen,lower alkyl having 1 - 5 carbon atoms, cycloalkyl or lower acyl and R₂is hydrogen or lower acyl.
 24. The method of claim 23 wherein R₁ ishydrogen or lower alkyl and R₂ is hydrogen or lower acyl.